The background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
Rit1 is a member in the subfamily of Ras-related GTPases as can be seen from the alignment of related Ras-type sequences shown in Prior Art FIG. 1A. Rit1 is involved in regulating p38 MAPK-dependent signaling cascades related to cellular stress, and is thought to cooperate with nerve growth factor to promote neuronal development and regeneration. Here, Rit1 seems to play a crucial role in coupling nerve growth factor (NGF) stimulation to the activation of both EPHB2 and MAPK14 signaling pathways and in NGF-dependent neuronal differentiation. Rit1 further seems involved in ELK1 trans-activation through the Ras-MAPK signaling cascade that mediates a wide variety of cellular functions, including cell proliferation, survival, and differentiation. Prior Art FIGS. 1B and 1C schematically illustrate involvement of Rit1 in various signaling pathways.
Rit1 is also known to be associated with certain diseases (e.g., Noonan syndrome) and certain cancers (e.g., lung cancer, colorectal cancer, thyroid cancer) and pheochromocytoma. More recently, somatic mutations in RIT1 were reported in a small proportion of lung cancer that clustered in a hotspot near the switch II domain of the protein (Oncogene 2014; 33, 4418-4423). Rit1 was also reported as a potential driver oncogene (Mol Cancer Ther 2013 12; C140), but no indication of any inhibitor was provided. In further reports, elevated expression of RITZ was shown to correlate with poor prognosis in endometrial cancer (Int J Clin Exp Pathol 2015; 8(9):10315-10324).
However, despite the at least tentative association with some malignancies and other diseases, no specific and effective Rit1 inhibitor has been reported to date. Therefore, there remains a need for compounds, compositions, and methods of inhibiting Rit1, particularly for the purpose of treating Rit1 associated diseases and cancer.